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Pediatric-inspired ALL therapy in adults age 18-60
However, outcomes in adults have been less encouraging, with historical 5-year relative survival <45% and 5-year overall survival <50% among adults under the age of 60.2,3 Several retrospective studies have suggested superior out- comes among adolescents and younger adults (AYA) treated on pediatric versus adult cooperative group studies.4-6 We and others have consequently investigated adapting pediatric ALL regimens for use in younger adults.7-12 One large, prospective US intergroup phase II clinical trial (Cancer and Leukemia Group B [CALGB] 10403, in collaboration with the Eastern Cooperative Oncology Group and SWOG), treated 295 AYA aged 17- 39 years with a true pediatric ALL regimen and observed 3-year event-free survival (EFS) of 59%, promising com- pared with historical controls.13 However, successfully adapting pediatric ALL therapy for adults over the age of 40 presents additional challenges and the upper age limit for safe administration of pegaspargase is not clearly defined, due in part to increasing risk of asparaginase- related toxicities with increasing age.8
L-asparaginase, a bacterial enzyme depleting serum asparagine, was historically a standard component of ALL therapy in children and AYA. In contrast to most healthy cells, ALL/LBL cells lack asparagine synthetase and are thus dependent on exogenous asparagine and uniquely sensitive to asparaginase.14 Randomized studies have demonstrated a survival benefit in pediatric patients treat- ed with asparaginase-containing regimens.15,16 However, asparaginase is associated with a host of toxicities, in part related to the above effects on protein synthesis, includ- ing hepatotoxicity, hypertriglyceridemia, hyperglycemia, hypofibrinogenemia, and thrombosis, as well as risks of hypersensitivity.17 Pegaspargase consists of polyethylene glycol covalently bound to the enzyme and may be asso- ciated with decreased immunogenicity and rates of hypersensitivity reactions compared with native E. coli asparaginase, and has a considerably longer half-life.18-20 Pegaspargase has been successfully incorporated into frontline treatment of pediatric patients and younger adults with ALL.7,19,21,22
We previously reported our experience utilizing a reg- imen incorporating two courses of induction chemother- apy and six doses of pegaspargase 2,000 IU/m2 at ≥4- week intervals, sequenced to avoid overlapping hepato- toxicity with other agents in adults with newly-diag- nosed ALL/LBL.7 We subsequently modified this regimen to exclude two myelosuppressive courses of consolida- tion and incorporated serial monitoring of minimal resid- ual disease (also known as “measurable residual disease,” MRD). Additional changes herein included higher doses of methotrexate (MTX, 3.5 g/m2 vs. 1 g/m2 for B- ALL/LBL; 5 g/m2 vs. 2.5 g/m2 for T-ALL/LBL) to reflect institutional experience that MTX doses ≥3.5 g/m2 are sufficient to treat lymphomatous leptomeningeal and brain involvement independent of intrathecal MTX, and as T lymphoblasts require a higher MTX dose to achieve optimal MTX/MTX-polyglutamate concentrations.23-25 Maintenance chemotherapy was extended from 2 to 3 years for all patients, as 3-year maintenance is commonly used for boys treated on pediatric protocols and adults broadly exhibit higher rates of relapse than children.26,27 Pegaspargase dose was uncapped, consistent with the prior study although capping at 3,750 IU/m2 was reported by others in an attempt to reduce toxicity.7,28 Herein, we present results of a phase II multi-center trial investigating
this approach in adults up to the age of 60 years with newly-diagnosed Philadelphia chromosome-negative (Ph- negative) ALL/LBL.
Methods
Clinical trial
From August 2014 to July 2017, patients with newly-diag- nosed, previously untreated Ph-negative precursor B-cell or T-cell ALL/LBL, aged 18-60 years, were enrolled at participating centers (see the Online Supplementary Methods for eligibility criteria and study design). Forty-three patients signed informed consent; four were determined ineligible prior to beginning treatment (Ph-posi- tive, n=2; mixed phenotype acute leukemia, n=2) and 39 patients received treatment on protocol.
The primary objective of the study was to determine rates of MRD negativity following induction phase I (Table 1). Secondary objectives including assessing rates of MRD negativity following induction phase II, rates of complete response (CR), overall sur- vival (OS), event-free survival (EFS), disease-free survival (DFS), and pegaspargase toxicities.
Toxicities were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
Regimen design
Study regimen details are summarized in Table 1. Treatment was adapted from the augmented arm of the Children’s Cancer Group 1882 protocol, with substitution of pegaspargase for native E. coli asparaginase and use of high-dose MTX (HD-MTX) inten- sification versus escalating (Capizzi) MTX,27 as previously report- ed.7 Pegaspargase was given after the second dose of HD-MTX in intensification I/II, and only after leucovorin rescue began. The protocol was approved by the Institutional Review Boards of all participating institutions.
Pegaspargase 2,000 IU/m2 IV (not capped) was administered over 1-2 hours at ≥4-week intervals. Hydrocortisone 100 mg intra- venous (IV) was given prior to each dose and 1-2 weeks of corti- costeroids followed each dose for hypersensitivity prophylaxis (Table 1). A specific pegaspargase toxicity management guideline was adopted; asparaginase enzyme activity and anti-asparaginase antibodies were measured at pre-specified time points (see the Online Supplementary Methods and the Online Supplementary Table S1).
Minimal residual disease assessment
MRD was assessed centrally in bone marrow (BM) aspirate samples using multiparameter flow cytometry (FACS) with sensi- tivity of at least 10-4. Any unequivocal evidence of residual ALL by FACS was considered as MRD positivity, even if <0.01% of BM mononuclear cells (see the Online Supplementary Methods; Online Supplementary Table S2; Online Supplementary Figure S1).
Statistical analyses
Incidence of grade 3-4 toxicities was compared between groups by age, sex, and BMI using Fisher’s exact test. OS, EFS, and DFS were computed using the Kaplan-Meier method and compared between groups using log-rank tests. EFS was defined as time from initiation of protocol therapy until date of morphologic relapse, confirmed refractory disease, or death from any cause; patients not known to have any of these events were censored on date of last follow-up. OS was defined as time from start of pro- tocol therapy to death from any cause, with surviving patients censored at last follow-up. Among patients achieving CR/CRi,
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